Variation in lung structure and function is principally derived from differential genetic regulation through development, and the regulatory pathways of multiple genetic determinants transcend environmental factors in regulating normal lung function. Specific genetic determinants, however, remain unknown. The central hypothesis of the current project suggests that variation in lung tenascin and elastin gene expression determines properties of differential lung structure and distensibility. This variation is particularly evident with respect to normal postnatal lung development and adverse genetic factors that lead to loss of lung elasticity. Specific Aim 1 focuses on studies that determine the role of parenchymal structure on the heterogeneity in lung distension and elasticity among inbred mouse strains. A broad spectrum of lung mechanical and structural traits will be measured to establish phenotypic differences that demonstrate the highest likelihood of being regulated by genetic determinants. Specific Aim 2 examines how gene regulation oftenascin and elastin production, reorganization and degradation regulates lung distension and elasticity. A series of genetic strategies including quantitative trait loci (QTL) analysis and gene expression profiling will identify a suite of candidate genes that regulate lung tenascin and elastin, and determine the role of specific genes in contributing to the heterogeneity of lung distensibility and elasticity. Specific Aim 3 will determine the roles of tenascin and elastin in lung development of alveolar structure and elasticity. Strain variation in lung mechanical and structural traits will be linked to established QTL and gene expression profiles as a function of developmental time. Given achievements in gene expression profiling and sequencing of mouse genomes, this proposal impacts the fields of lung biology and lung mechanics by describing differential gene regulation of tenascin and elastin, and their contributions to variation in lung structure and elasticity.